Chemistry And Structureactivity Relationship

The typical local anesthetics contain hydrophilic and hydrophobic moieties that are separated by an intermediate ester or amide linkage (Figure 14-1). A broad range of compounds containing these minimal structural features can satisfy the requirements for action as local anesthetics. The hydrophilic group usually is a tertiary amine but also may be a secondary amine; the hydrophobic moiety must be aromatic. The nature of the linking group determines some of the pharmacological properties of these agents. For example, local anesthetics with an ester link are hydrolyzed readily by plasma esterases.

Hydrophobicity increases both the potency and the duration of action of the local anesthetics because association of the drug at hydrophobic sites enhances the partitioning of the drug to its sites of action and decreases the rate of metabolism by plasma esterases and hepatic enzymes. In addition, the receptor site for these drugs on Na+ channels is thought to be hydrophobic, so that receptor affinity for anesthetic agents is greater for more hydrophobic drugs. Hydrophobicity also increases toxicity, so that the therapeutic index is decreased for more hydrophobic drugs.

Molecular size influences the rate of dissociation of local anesthetics from their receptor sites. Smaller drug molecules can escape from the receptor site more rapidly. This characteristic is important in rapidly firing cells, in which local anesthetics bind during action potentials and dissociate during the period of membrane repolarization. Rapid binding of local anesthetics during action potentials causes the frequency- and voltage-dependence of their action.

MECHANISM OF ACTION Local anesthetics block conduction by decreasing or preventing the large transient increase in the permeability of excitable membranes to Na+ that normally is produced by a slight depolarization of the membrane (see Chapter 12). This action is due to direct interaction with voltage-gated Na+ channels. As the anesthetic action progressively develops in a nerve, the threshold for electrical excitability gradually increases, the rate of rise of the action potential declines, impulse conduction slows, and nerve conduction eventually fails.

Local anesthetics can block K+ channels at higher concentrations of drug; thus, blockade of conduction is not accompanied by any large or consistent change in resting membrane potential.

Quaternary analogs of local anesthetics block conduction when applied internally to perfused giant axons of squid but are relatively ineffective when applied externally, suggesting that the site at which local anesthetics act, at least in their charged form, is accessible only from the inner surface of the plasma membrane. Therefore, local anesthetics applied externally first must cross the membrane before they can exert a blocking action.

The major mechanism of action of these drugs involves their interaction with one or more specific binding sites within the Na+ channel (Figure 14-2).

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